Sodium oxybate, currently approved at a 500 mg/ml dose for narcolepsy-associated cataplexy and excessive daytime sleepiness, is a central nervous system depressant and carries a boxed warning against its use in combination with other similar drugs.

The label information also warns that sodium oxybate is a drug known to be abused.

Members of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee will be asked if the data show that the drug is effective in treating fibromyalgia, and if it improves sleep in fibromyalgia patients.

The committee also will be asked whether there are safety concerns with Jazz Pharmaceuticals' marketing plan: to lower the concentration of the drug to 375 mg/ml and give it a different brand name -- Rekinla -- to treat fibromyalgia.

In its background materials, the FDA reviewers noted that Jazz has proposed a risk evaluation and mitigation strategy (REMS) for the new indication "that builds on an existing program for Xyrem," the narcolepsy drug. "In order to address the risk of abuse, misuse, and overdose, the program includes enrollment of prescribers and distribution through 15 specialty pharmacy providers that would have to be certified," the reviewers wrote.

To avoid confusion between the different drug names, the company has proposed different but similar programs for each indication, the FDA staff said. In its materials, Jazz Pharmaceuticals noted that no certified pharmacy will dispense the drug for both indications -- they will either dispense for one or the other.

But the reviewers added that "the existence of two REMS programs for the same established name may create confusion among prescribers who treat patients for both narcolepsy and fibromyalgia. The same established product with two enrollment forms and two pharmacy dispensing mechanisms based on treatment indication may be confusing for prescribers, pharmacies, and patients and may be burdensome to the healthcare system."

The agency staff also expressed concern that the 375 mg/ml dosage might be a source of potential dosing errors. "The number is cumbersome for Rekinla's dose calculations and when converting the dose from milligrams to the corresponding volume in milliliters," the reviewers wrote.

Although Jazz said it selected the dosage "for patient dosing convenience and manufacturing efficiency" and to "minimize bottles and components to be dispensed each month," the company doesn't substantiate either of these reasons in its application, according to the staff reviewers.

In addition, "when considering this risk of dose calculation errors, we believe that the numerical value '375' is cumbersome when calculating the doses," they continued.

"Neither patients nor practitioners are likely to accurately calculate, for example, the volume of Rekinla 375 mg/mL oral solution that will deliver a 2.25 gram dose without the aid of a calculator. Even with aid of a calculator, the multistep calculation is more complex than what would be required for the 500 mg/mL concentration of sodium oxybate and therefore more prone to error."

FDA staff did note that Jazz Pharmaceuticals "has provided substantial evidence of effectiveness in two phase 3, adequate and well-controlled trials which demonstrated that Xyrem reduced pain in patients diagnosed with fibromyalgia."

However, they added that they believed the data did not support the company's proposed claim for improved sleep.

In one of the trials, involving 548 patients randomized to placebo or 4.5 g or 6 g per night of the drug, researchers reported the following improvements relative to baseline:

The results were reported in April at the annual meeting of the American Academy of Neurology.

Xyrem's safety profile for fibromyalgia, which was tested in more than 1,060 treated patients in doses up to 9 g per night, appears to be acceptable, the FDA reviewers said, noting that "the adverse event profile appears acceptable across the to-be-marketed dose range and is generally consistent with that seen in the currently approved Xyrem for narcolepsy."

Treatment-emergent adverse events leading to discontinuation in the efficacy studies occurred in 19% of sodium oxybate-treated patients, compared with 8% of placebo-treated patients.

Nervous system disorders such as headache, dizziness, and somnolence were most common (7%), followed by psychiatric disorders (6%) and GI disorders (6%).

The manufacturer noted in its materials that "in the fibromyalgia clinical studies with sodium oxybate, there were no adverse events indicative of abuse, dependence, misuse, or severe withdrawal symptoms with use of sodium oxybate. There was one event of overdose in which a patient with narcolepsy took 15 times the maximum dose; the patient recovered without sequelae."

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